Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.6.4 (chondroitinase)
 2,039 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Correlations have been noted between the expression of certain alternatively spliced CD44 isoforms and the metastatic propensity of various histologically distinct tumor cell types. The precise mechanism by which particular CD44 isoforms contribute to the metastatic process is, however, unclear. In the present study we demonstrate that CD44R2, a CD44 isoform highly expressed on activated and transformed hemopoietic cells, can recognize and bind a common determinant present on CD44H and CD44R1. Importantly, CD44H lacked this activity. Pretreatment of TIL1 cells expressing CD44H or CD44R1 with chondroitinase ABC inhibited adhesion to CD44R2, suggesting that the unique inserted region present within the CD44R2 molecule, encoded by exon v10, mediates cell adhesion by potentiating the recognition of chondroitin sulfate moieties presented in association with other CD44 molecules. These data help explain the differential involvement of v10-containing CD44 isoforms in tumor metastasis.
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PMID:Alternatively spliced CD44 isoforms containing exon v10 promote cellular adhesion through the recognition of chondroitin sulfate-modified CD44. 1009 37

Intact fibronectin (FN) protects cells from apoptosis. When FN is fragmented, specific domains induce proteinase expression in fibroblasts. However, it is not known whether specific domains of FN can also regulate apoptosis. We exposed fibroblasts to four recombinant FN fragments and then assayed for apoptosis using criteria of cellular shape change, condensed nuclear morphology, and DNA fragmentation. The fragments extended from the RGD-containing repeat III10 to III15; they included (V(+)) or excluded (V(-)) the alternatively spliced V region and contained either a mutated (H(-)) or an unmutated (H(+)) heparin binding domain. Only the V(+)H(-) fragment triggered decreases in pp125(FAK) levels and apoptosis, which was rescued by intact FN and inhibitors of caspase-1 and caspase-3. This apoptotic mechanism was mediated by a chondroitin sulfate proteoglycan, since treating cells with chondroitin sulfate or chondroitinase reversed the apoptotic cell shape changes. The alpha4 integrin receptor may also be involved, since using a blocking antibody to alpha4 alone induced apoptotic cell shape changes, whereas co-treatment with this antibody plus V(+)H(+) reversed these effects. These results demonstrate that the V and heparin binding domains of FN modulate pp125(FAK) levels and regulate apoptosis through a chondroitin sulfate proteoglycan- and possibly alpha4 integrin-mediated pathway, which triggers a caspase cascade.
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PMID:Mutations in the heparin binding domain of fibronectin in cooperation with the V region induce decreases in pp125(FAK) levels plus proteoglycan-mediated apoptosis via caspases. 1052 84

Previous in vitro studies have shown CD44 isoforms containing the alternatively spliced exon v3 (CD44v3) to be modified with heparan sulphate (HS) and to bind HS-binding basic fibroblast growth factor (bFGF). Here, we demonstrate that exogenously added bFGF is also bound in vivo by CD44v3-positive keratinocytes in normal skin and by tumour cells in basal cell carcinoma and squamous cell carcinoma (SCC), two skin cancers of keratinocyte origin. bFGF binding and CD44v3 expression were colocalized in cultured human normal keratinocytes (HNK) and on the SCC cell line A431. By contrast, benign or malignant tumours of melanocyte origin failed to express CD44v3 and bound no bFGF. The bFGF binding to normal or transformed keratinocytes in vivo and in vitro was dependent on HS modification, as it was completely eliminated by pretreatment with heparitinase or by blocking with free heparin, whereas chondroitinase had no effect. In addition, specific removal of CD44v3 by antibody-induced shedding also diminished bFGF binding to keratinocytes. Furthermore, bFGF stimulated the proliferation of CD44v3-positive HNK and A431 in a dose-dependent fashion. This bFGF effect was again completely abolished by heparitinase or free heparin, but not by chondroitinase. In aggregate, our results suggest that a function of HS-modified CD44 isoforms such as CD44v3 in skin is to present the HS-binding growth factor bFGF, thereby stimulating the proliferation of normal or transformed keratinocytes.
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PMID:Colocalization of basic fibroblast growth factor and CD44 isoforms containing the variably spliced exon v3 (CD44v3) in normal skin and in epidermal skin cancers. 1058 62

Sequencing of cDNA clones has shown that the carboxy terminal domain of the core protein of large proteoglycans (aggrecans) from human cartilage contains an epidermal growth factor-like (EGF-like) domain which is alternatively spliced. In a previous study it was found that the domain of the translated protein can be recognized by polyclonal antibodies to mouse EGF. A competitive enzyme-linked immunoabsorbent (ELISA) assay has been developed to evaluate the EGF-like domain content of aggrecans at various ages and in osteoarthritis. Fetal aggrecans digested with protease free chondroitinase ABC were adsorbed on polyvinyl chloride microtiter plates followed by blocking with bovine serum albumin and goat serum. Mixtures of known amounts of protein of digested aggrecans and constant amounts of anti-mouse EGF antibodies were incubated and added to plates. The second antibody was peroxidase-conjugate F(ab')2. Fetal, newborn and child aggrecan proteins have a higher content of EGF-like domain than aggrecan proteins from cartilage of older humans. Three areas of cartilages from osteoarthritic joints were separated: cartilages with normal macroscopic appearance, erosion border cartilage and osteophytic cartilage. Values derived from these samples were compared with values derived from nonosteoarthritic aged humans. The content of aggrecans from osteoarthritic cartilage with normal macroscopic appearance was similar to or slightly lower than the latter. The aggrecans from osteophytes had a higher EGF-like domain content. The aggrecans from the erosion border had a variable content, close to noneroded cartilages, to osteophytes or in between the values obtained for noneroded cartilages and for osteophytes. Variations in the amount of newly synthesized aggrecans, in the proteolysis of the carboxy terminal domain of aggrecans and in the alternating splicing of the EGF-like domain might explain the results shown here.
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PMID:The epidermal growth factor-like domain of the large proteoglycans from articular cartilage (aggrecans). Estimate of content at different ages and in osteoarthritis. 1544 24